Our objective is to expand our ongoing work concerning the modulary influence of enkephalin systems on behaviors mediated by the nigrostriatal and mesolimbic dopamine (DA) systems of the CNS. Our approach is to combine the quantification of DA-mediated behaviors with sensitive measures of DA release and postsynaptic receptor status in rats. By means of push-pull cannulation and high performance liquid chromatography, we will measure alterations in the release of DA and production of metabolites as a function of acute and chronic opiate administration, and in states of post-treatment hypersensitivity. We will use receptor binding assays in combination with chemical lesion techniques to determine whether enkephalin receptors are located on DA axon terminals in the mesolimbic system. With other binding assays we will assess changes in postsynaptic DA receptors in the two systems as a function of various schedules of chronic opiate treatment, and correlate these changes with behavioral measures of hypersensitivity. Using intracranial self-stimulation to independently quantify activity in the two systems, we will investigate the effects of parenteral administration of DA agonists and opiates, alone and in combination, and the effects of central infusion of these agents into the axon terminal region of the system being self-stimulated. Finally, we will study DA-opiate interactions in subjects rendered hypersensitive in one or the other neurotransmitter system by chronic treatment with their respective antagonist agents. To expand our understanding of enkephalinergic-dopaminergic interactions is clinically relevant, in view of the role of the two DA systems in such disease states as Parkinsonism schizophrenia, and neuroleptic-induced tardive dyskinesia.